PROJECT SUMMARY Chemotherapy-induced cognitive dysfunction (referred to as chemobrain) negatively impacts cancer survivors and has emerged as a significant medical problem. To date, no effective treatment exists due to the limited understanding of the mechanisms that drive chemotherapy-induced cognitive impairments. To provide effective therapeutic strategies for this emergent medical problem, this application aims to answer Provocative Question #12: What are the molecular and cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae? While the underlying molecular pathways vulnerable to chemotherapy-induced neurotoxicity are not well understood, recent results from our laboratory indicate the Nampt-mediated NAD+ pathway is a promising therapeutic target for chemobrain. Using the platinum-based chemotherapy compound cisplatin, we demonstrate its efficacy in suppressing the nicotinamide phosphoribosyl transferase (Nampt)-mediated NAD+ metabolic pathway. Cisplatin-mediated suppression of Nampt-NAD+ metabolism leads to neurogenic dysfunction of the adult mouse hippocampus and memory impairments. Remarkably, we found that by increasing NAD+ levels via administration of the NAD+ precursor nicotinamide mononucleotide (NMN), we can effectively reverse cisplatin-induced deficits in neuronal dendrite morphology and memory function, thus emphasizing the therapeutic potential of NAD+ metabolism in amelioration of chemobrain. Based on these observations, our central hypothesis is that increasing Nampt or NAD+ levels prevent cisplatin-induced impairments in neuronal and cognitive function. Our findings represent a novel therapeutic strategy for chemobrain. To test this novel hypothesis, Aim 1 will determine whether increasing NAD+ levels through NMN supplementation can improve cisplatin-induced deficits in neuronal and cognitive function in both young and aged mice. In addition, our translational proposal will ensure the safety of NMN, as we will determine if NMN has a detrimental impact on anti-neoplastic activity of cisplatin using patient-derived xenograft (PDX) mouse models. Subsequently, Aim 2 will elucidate if genetically increasing Nampt levels can prevent impairments in neuronal morphology and cognitive function. We will also evaluate if P7C3, a Nampt enzyme activity enhancer, can improve cisplatin-induced chemobrain in young and aged mice. Our proposed work will provide critical pathophysiological mechanisms and improve our understanding of the Nampt-mediated NAD+ metabolic pathway in order to improve chemotherapy-induced cognitive dysfunction. Ultimately, the findings will provide a framework by which safe and effective therapeutic strategies may be utilized in patients undergoing cancer treatment so as to minimize or reverse neuronal and memory dysfunction.